tbuckley/cabot-search huggingface dataset:
In silico approaches to patient selection: Credentialing elraglusib as a novel treatment in metastatic melanoma resistant to checkpoint inhibitors.
Authors: Joseph McDermott, Taylor Weiskittel, Brittany Borden, Ludimila Cavalcante, Francis J. Giles, Benedito A. Carneiro, Hu Li, Andrew Paul Mazar
Journal: Journal of Clinical Oncology (2023)

3079 Background: Elraglusib (9-ING-41), a novel inhibitor of GSK-3β, has been evaluated in &gt;230 patients (pts) with advanced malignancies including metastatic melanoma in the 1801 phase 1/2 trial (NCT03678883). Pts with melanoma treated with single agent elraglusib demonstrated clinical benefit including a durable complete response despite multiple prior lines of therapy including checkpoint inhibitors (CPI). Methods: We collected data from numerous -omic modalities in the 1801 trial to characterize markers of elraglusib response with bioinformatics and machine learning (ML). Genomic panels were collected on 105 pts. The most frequent tumor types included colorectal cancer (n=35), pancreas (n=31), lung (n=15) and metastatic melanoma (n=12). Pts were treated with elraglusib as a single agent or in combination with chemotherapy. Pathway based features were generated by quantifying the percent of each Reactome pathway that was mutated. These pathway features were iteratively evaluated for their performance in shallow neural networks predicting patient RECIST with each model using 5-15 randomly selected features at a time. Publicly available genomic data from an anti-PD-1 trial in patients with metastatic melanoma (Hugo et al., 2017) was transformed into pathway-based features and input into the final model to predict elraglusib response in this population. Results: Our final pathway based genomic model for elraglusib response performed with a training accuracy of 93% and a test accuracy of 88% on the 1801 patients. We then tested the model on metastatic melanoma patients who were treated with anti-PD-1 therapy. We found that patients from Hugo et al. were predicted to respond to elraglusib (22/26). In addition, most patients with tumors resistant to anti-PD-1 therapy were also predicted to respond to elraglusib (10/12). Finally, we tested the model on metastatic melanoma patients treated with elraglusib in the 1801 study that had failed CPI and for whom -omic data was available. The model correctly identified 5/5 patients that demonstrated clinical benefit (1 CR, ongoing&gt;1400 days; 4 prolonged OS of 107, 256, 357, and 556 days). Conclusions: We applied robust in-silico modeling developed using 1801 trial data to develop a rationale for the development of elraglusib in the treatment of metastatic melanoma including patients that failed or were refractory to anti-PD-1 treatment. This model correctly identified metastatic melanoma patients in 1801 with good clinical outcomes that had failed prior CPI treatment. Further, we present this in silico approach as a robust way to repurpose prior clinical study genomics and ML modeling for population enrichment during the clinical development of novel drugs. Clinical trial information: NCT03678883 .
The impact of DNA damage repair gene mutations on therapeutic response among Chinese patients diagnosed with advanced biliary tract cancer.
Authors: Hongfeng Gou
Journal: Journal of Clinical Oncology (2023)

e16190 Background: Biliary tract cancer (BTC) is a fatal disease characterized by molecular heterogeneity, which results in variations in biological behavior. Despite this, the knowledge of pathogenic alterations in the Chinese BTC population using next-generation sequencing (NGS) profiles remains limited. Therefore, we performed a retrospective investigation to assess the predictive significance of DNA damage repair (DDR) mutations in facilitating precision medicine for this disease. Methods: NGS profiling was carried out on resected tissues obtained from Chinese patients diagnosed with advanced BTC. In addition, baseline clinical and genetic characteristics were collected, along with data on their survival outcomes. Results: A total of 68 Chinese patients with BTC who received ﬁrst-line platinum-containing chemotherapies were enrolled in this study [intrahepatic cholangiocarcinoma (ICC), 33; extrahepatic cholangiocarcinoma (ECC), 13; gallbladder carcinoma (GBC), 22]. Genetic alterations were observed in 67 patients (98.5%), with TP53 (50.0%), KRAS (26.8%), ARID1A (16.2%), and CDKN2A (16.2%) being the most commonly mutated genes. Patients with TP53 mutations demonstrated a trend towards reduced median OS (16.6 vs. 20.1 months, P=0.145). Mutations in DDR genes were identified in 29 (42.6%) of overall patients, primarily involving ATM (11.8%) and BAP1 genes (8.8%), and were signiﬁcantly associated with longer mPFS (6.4 vs. 4.8 months, P=0.022) and mOS (21.2 vs. 14.3 months, P=0.011) in patients who received ﬁrst-line platinum-containing chemotherapies. DDR-mutated patients treated with PD-1 blockades showed a tendency towards improved overall survival compared to the DDR-naive group (20.8 vs. 14.3 months, P=0.297). Furthermore, tumor mutational burden (TMB) could be estimated in 63 cases and was signiﬁcantly higher in those with DDR mutations (P=0.029). Conclusions: Genetic information can aid in identifying a subgroup of BTC patients who may benefit from targeted therapy, this retrospective study demonstrated the predictive significance of DDR mutations for platinum-based chemotherapy efficacy in Chinese patients. Nonetheless, additional research is necessary to explore the potential of DDR mutations in predicting sensitivity to PD-1 blockade.
Genomic determinants of progression-free survival after second line of therapy (PFS-2) for patients on immunotherapy-based combination therapies for advanced clear cell renal cell carcinoma.
Authors: Kelly N. Fitzgerald, Ritesh R Kotecha, Andrea Knezevic, Natalie Shapnik, David H Aggen, Maria Isabel Carlo, Neil J. Shah, Martin H Voss, Darren R. Feldman, Robert J. Motzer, Chung-Han Lee
Journal: Journal of Clinical Oncology (2023)

4545 Background: The role of somatic genomic mutations in predicting outcomes in clear cell renal cell carcinoma (ccRCC) is poorly defined. Both ipilimumab/nivolumab (IO/IO) and several combinations of VEGFR-targeted tyrosine kinase inhibitor (TKI/IO) are preferred first-line treatment options for metastatic ccRCC. The impact of somatic mutations on PFS-2 for IO combination therapies was evaluated in this retrospective analysis. Methods: One-hundred forty-one patients with ccRCC had sequencing with MSK-IMPACT and initiated 1 st line combination IO at Memorial Sloan Kettering (MSK) Cancer Center between 1/1/2014 and 12/30/2020. Treatment groups are defined as IO/IO (n=76) and TKI/IO (n=65). PFS-2 is defined as time from start of 1 st line to progression on next therapy, or death, and is estimated using Kaplan-Meier method. PFS-2 association with each mutation was assessed via log-rank test and a model-based approach. Restricted mean survival time (RMST) up to 48 months was calculated for PFS-2 and modeled using a generalized linear model adjusted for IMDC risk. To test for heterogeneity of effect among treatment groups, an interaction test between somatic mutation and treatment group is performed in the model. Results: VHL, PBRM1, SETD2, mTOR pathway, BAP1, and TP53 were the most common somatic mutations. Only BAP1 was significantly associated with PFS-2: median PFS-2 was 44 months for patients without BAP1 mutation and 17 months for patients with BAP1 mutation (log-rank p=0.006). After adjusting for IMDC risk group, 48 month RMST for PFS-2 was 13 months lower in patients with BAP1 mutation. An interaction test performed in the RMST model showed no significant variation in the treatment effect of IO/IO or TKI/IO based on the presence or absence of BAP1 mutation (p=0.97), although sample size limits power to detect differences. Results for other somatic mutations are shown. Conclusions: PFS-2 was significantly inferior for ccRCC patients with somatic BAP1 mutation treated with IO-based therapy. Interaction test did not suggest a significant advantage for IO/IO or TKI/IO for mutation-present or -absent groups. Clinical stratification remains key for selecting TKI/IO or IO/IO for patients. [Table: see text]
Phase 1 study of ziftomenib (KO-539) in combination with venetoclax or venetoclax/azacitidine or standard induction cytarabine/daunorubicin (7+3) chemotherapy for the treatment of patients with acute myeloid leukemia.
Authors: Amer Methqal Zeidan, Amir Tahmasb Fathi, Ghayas C. Issa, Harry Paul Erba, Julie Ahsan, Daniel Corum, Blake E. Tomkinson, Tom Kozlek, Mollie Leoni, Eunice S. Wang
Journal: Journal of Clinical Oncology (2023)

TPS7079 Background: Relapsed or refractory (R/R) acute myeloid leukemia (AML) with nucleophosmin 1-mutations ( NPM1-m) or KMT2A-rearrangment ( KMT2A-r) represent a high unmet need. Ziftomenib is a potent and selective inhibitor that targets the menin-mixed-lineage leukemia (MLL) lysine[K]-specific methyltransferase 2A ( KMT2A) interaction driving leukemogenesis in these subtypes. An ongoing Phase 1/2 study (KO-MEN 001) has demonstrated meaningful clinical activity and tolerability with ziftomenib monotherapy in R/R AML. In preclinical testing, ziftomenib combined with venetoclax induced synergistic lethality in KMT2A-r and NPM1-m human AML cell lines and patient-derived cells. Moreover, treatment with ziftomenib plus venetoclax/azacitidine has induced prolonged durable remissions in mice with KMT2A-r AML xenografts. Therefore, administration of ziftomenib in combination with standard-of-care (SOC) therapies may provide additional clinical benefit for patients with newly diagnosed or R/R NPM1-m and KMT2A-r menin-dependent AML. Methods: KOMET-007 (KO-MEN-007, NCT# ) is a 2-part dose escalation (Phase 1a) and expansion (Phase 1b) study to evaluate the safety, tolerability, and preliminary antileukemic activity of ziftomenib in combination with non-intensive chemotherapy (NIC) and intensive chemotherapy (IC) in patients with NPM1-m and KMT2A-r AML. During Phase 1a, the ziftomenib dose will be escalated with standard doses of either venetoclax and azacitidine (zifto/ven/aza) or cytarabine and daunorubicin (zifto/7+3) in defined genetic cohorts ( NPM1-m and KMT2A-r) using a rule-based approach (n = 6 per cohort/dose level) to select ziftomenib doses for expansion/validation in Phase 1b. The Phase 1b portion will also evaluate zifto/ven/aza in newly diagnosed AML ( KMT2A-r and NPM1-m) and zifto/ven in R/R AML ( NPM1-m only). The overall primary objectives are to establish the minimum biologically effective, dose limiting toxicities, and recommended Phase 2 dose of ziftomenib combined with NIC and IC backbones in each genetically defined cohort. Additional secondary endpoints include preliminary antileukemic efficacy (including MRD-negative responses and number of patients able to transition to subsequent allogeneic stem cell transplant), pharmacokinetic, and pharmacodynamic data. Exploratory end points include biomarkers for efficacy and resistance, pharmacodynamic biomarkers and activity in isolated myeloid sarcoma. Clinical trial information: NCT04067336 .
Long-term outcome of neoadjuvant mFOLFOX6 with or without radiation versus fluorouracil plus radiation for locally advanced rectal cancer: A multicenter, randomized phase III trial.
Authors: Jianwei Zhang, Pan Chi, Ping Lan, Long Cui, Hongbo Wei, Ren Zhao, Zhongcheng Huang, Hao Zhang, Yue Cai, Jianping Wang, Yanhong Deng
Journal: Journal of Clinical Oncology (2023)

3505 Background: Pevisous results of phase III FOWARC trial demonstrated that mFOLFOX6, with or without radiation, did not significantly improve survival versus fluorouracil with radiation in patients with locally advanced rectal cancer at 3 yeas. Here, we presented the data of long-term disease free survival (DFS) and overall survival (OS). Methods: In this multicenter, phase III trial, patients with stage II/III rectal cancer were randomly assigned (1:1:1) to receive 5 cycles of infusional fluorouracil (leucovorin 400 mg/m2, fluorouracil 400 mg/m2, and fluorouracil 2.4 g/m2 over 48 hours) plus radiotherapy (46.0 to 50.4 Gy delivered in 23 to 25 fractions during cycles 2 to 4) followed by surgery and seven cycles of infusional fluorouracil adjuvant treatment, mFOLFOX6 plus radiotherapy, or four to six cycles of mFOLFOX6 followed by surgery and six to eight cycles of mFOLFOX6. Results: Totally, 495 patients were enrolled,165 pateints in each group. 445 patients underwent surgery. After a median follow-up of 9.5 years, DFS events were observed in 56, 54, and 55 patients in fluorouracil plus radiotherapy, mFOLFOX6 plusradiotherapy, and mFOLFOX6 goups. The 10-year DFS rate were 55.5%, 63.0% and 62.8% (P = 0.934 by the log-rank test). OS evets were reported in 39, 38, and 40 patientts in the 3 group. The 10-year OS rate was 66.2%, 73.2% and 73.0% (P = 0.919 by the log-rank test), respectively. Conclusions: With long-term follow up, no significant difference in was found in survival outcome between mFOLFOX6, with and without radiation. Comparing with fluorouracil plus radiation, mFOLFOX6 plus radiation also failed to improve long-term survival. Clinical trial information: NCT01211210 .
Oncologic outcomes in patients with radiation associated rectal adenocarcinoma.
Authors: Dana Mohamed Rashid Omer, Floris S Verheij, Anisha Luthra, Roni Rosen, Hannah M Thompson, Paul Bernard Romesser, Philip Paty, Julio Garcia-Aguilar, Francisco Sanchez-Vega
Journal: Journal of Clinical Oncology (2023)

e15529 Background: The rectal wall is often irradiated during pelvic radiotherapy for prostate cancer, potentially increasing the risk of rectal adenocarcinoma. The oncologic outcomes of rectal adenocarcinoma in previously irradiated patients remain largely unknown. Methods: We performed a retrospective analysis of patients with stage I-IV rectal adenocarcinoma after radiotherapy for prostate cancer (RCRPC). Clinical characteristics and treatment were compared to a background set of patients with rectal cancer not associated with prostate cancer (RCNAPC). We investigated the differences in survival using propensity score matching (1:1 ratio). Patients were matched based on stage, tumor size, distance from anal verge and circumferential tumor location, but were unable to be matched on age. Five-year disease-free survival (DFS), overall survival (OS), local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) were visualized using Kaplan-Meier curves and statistical significance was assessed using log-rank tests. Results: The study included 66 RCRPC patients treated with prostate brachytherapy (n = 19), external beam radiation therapy (n = 31) or both (n = 16). The median latency period between the completion of prostate radiotherapy and the diagnosis of rectal cancer was 11.7 years. The median follow-up from rectal cancer diagnosis was 2.4 years. The median prostate radiation dose was 74 Gy. Compared to the 609 RCNAPC patients, the RCRPC group was older (median 78 vs 55 years, P &lt; 0.001) and more likely to be stage I (24% vs 5%, P &lt; 0.001). Tumors were more frequently found within the distal rectum (47% vs 22%, P &lt; 0.001) and along the anterior rectal wall (33% vs 11%, P &lt; 0.001). Patients in the RCRPC group were less likely to receive neoadjuvant chemotherapy (50% vs. 93%, P &lt; 0.001), neoadjuvant radiation (21% vs 85%, P &lt; 0.001), or undergo surgery (54% vs 61%, P &lt; 0.001) compared to the RCNAPC group. The oncologic outcomes for the RCRPC group and matched cohort of patients with RCNAPC are presented in table 1. Conclusions: Patients with radiation associated rectal cancer have earlier stage tumors but show higher rates of distant metastasis and lower survival compared to nonirradiated patients. They are older and less likely to receive chemotherapy or radiation and are often poor candidates for radical surgery. Whether the worse outcomes are attributable to differences in patient characteristics, available treatment options or a more aggressive biology remains unknown. [Table: see text]
Efficacy and safety of regorafenib + PD-1 inhibitor combined with local therapy as second-line treatment in patients with advanced hepatocellular carcinoma: A multicenter retrospective real-world study.
Authors: Xiaobo Fu, Maoyuan Mu, Han Qi, Weiwei Jiang, Zixiong Chen, Fei Gao
Journal: Journal of Clinical Oncology (2023)

e16159 Background: Regorafenib and PD-1 inhibitor both are recommended as the standard second-line treatment for advanced hepatocellular carcinoma (HCC) in currently authorized guidelines. Local interventional therapies showed significant benefits in the treatment of HCC. We aimed to evaluate to investigate the efficacy and safety of regorafenib + PD-1 inhibitor combined with intervention therapy as the second-line treatment option for advanced HCC. Methods: From October 2019 to February 2022, 31 patients with advanced HCC treated with regorafenib+PD-1 were retrospectively included. All patients were divided into two groups: group A (n = 17, patients received regorafenib +PD-1 combined with local therapy), and group B (n = 14, patients received regorafenib+PD-1). The inclusion criteria are as follows: the first-line treatment was sorafenib or lenvatinib; advanced HCC (BCLC-C); ECOG score was 0-1; Child-Pugh score was 5-7; at least one measurable lesion; expected survival time ≥ 3 months. The treatment efficacy was evaluated by modified-RECIST. Objective response rate (ORR) and disease control rate (DCR) were evaluated in two groups. Major complications referred to those that result in death or serious adverse effects including sepsis, uncontrollable bleeding, and acute renal failure; others were considered minor complications. Results: The median follow-up time was 12.9 months. The median PFS was 8.3 months vs. 7.5 months (p = 0.814). The median TTP (Time to Progression) time was 8.3 months vs. 7.5 months (p = 0.973). In group A, eleven patients received TACE, 2 received thermal ablation, and 4 received HAIC. In group A: four patients reached PR (Partial response), and 7 patients stayed SD (Stable disease), while six patients suffered tumor progression (PD, Progression disease); In group B, only one patient reached PR, and 7 patients stayed SD, 6 patients suffered tumor progression. The ORR was 23.5% (group A) vs. 7.1% (group B), respectively. The DCR was 64.7% (group A) vs 57.1% (group B), respectively. The daily dose of Regorafenib was 80mg (58.8%), 120mg (29.4%), and 160mg (11.8%), respectively in group A. The daily dose of Regorafenib was 80mg (57.1%), 120mg (28.5%), and 160mg (14.3%), respectively in group B. The dose for the PD-1 inhibitor was 200mg (every three weeks). Adverse events of systemic drugs in group A and group B were 58.8% (10/17), and 35.7% (5/14), respectively. Hand–foot skin reaction was the most common adverse event in both groups (47.1% (8/17) vs 35.7% (4/140), respectively). No major complications of local therapies were observed in both groups. Conclusions: Regorafenib+PD-1 combined with local therapy as the second-line treatment option for advanced HCC may be effective and safe and provides better benefits than regorafenib+PD-1 alone.
Estimated net benefit of avelumab (AVE) + best supportive care (BSC) vs BSC alone for patients (pts) with advanced urothelial carcinoma (aUC) using a quality-adjusted time without cancer symptoms or toxicity (Q-TWiST) analysis.
Authors: Thomas Powles, Paul Cislo, Melissa Kirker, Jane Chang, Norbek Gharibian, Allison Thompson, Nuno Costa, Petros Grivas
Journal: Journal of Clinical Oncology (2023)

4515 Background: The JAVELIN Bladder 100 (JB-100) trial (NCT02603432) showed that treatment with AVE first-line maintenance (1LM) + BSC significantly prolonged overall survival (OS) and progression-free survival (PFS) vs BSC alone in pts with aUC that had not progressed after 1L platinum-based chemotherapy. Safety and patient-reported outcomes (PROs) were previously reported. This post hoc analysis used JB-100 data to assess between-treatment differences using a Q-TWiST analysis, an integrated measure that incorporates efficacy, safety, and PROs into a single value. Methods: Mean OS was partitioned into 3 health states: time with all-cause grade ≥3 toxicity (TOX) prior to progression, time without all-cause grade ≥3 toxicity or symptoms of disease progression (TWiST), and time after progression or relapse (REL). To ensure equal observation time for each arm, analysis time was restricted to a period of 47.7 months from randomization, which was the shorter follow-up time between arms. A range of utility values were explored and weighted by the time in each health state then summed to estimate Q-TWiST to account for differences in quality of life. Mean between-treatment differences for each health state were also calculated. Bootstrap methods were used to estimate CIs for means and difference between means. Results: Time in TOX was slightly longer with AVE + BSC vs BSC alone; however, time spent in TWiST was much longer with AVE + BSC. Time in REL with AVE + BSC appears shorter vs BSC alone because pts experienced more time in the progression-free state, which led to less time in REL. Regardless of the range of utility values explored for each health state, the Q-TWIST estimate was always longer with AVE + BSC, with mean differences ranging from 3.7 to 7.1 months (95% CI not including 1). Conclusions: Pts receiving AVE + BSC demonstrated a consistently longer Q-TWiST (vs BSC alone), indicating a net benefit. Pts receiving AVE + BSC achieved greater quality-adjusted time by progressing more slowly (shorter REL) and living longer (greater OS). The Q-TWiST advantage reflects the safety profile of AVE in the context of a survival benefit. Restricted health state durations in months (mean, 95% CI). Clinical trial information: NCT02603432 . [Table: see text]